1. Field of the Invention
The invention relates to the field of medical informatics, and more particularly to a system and method using medical informatics primarily to plan, conduct and analyze clinical trials and their results.
2. Description of Related Art
Over the past number of years, the pharmaceutical industry has enjoyed great economic success. The future, however, looks more challenging. During the next few years, products representing a large percentage of gross revenues will come off patent, increasing the industry's dependence upon new drugs. But even with new drugs, with different companies using the same development tools and pursuing similar targets, first-in-category market exclusivity has also fallen dramatically. Thus in order to compete effectively in the future, the pharmaceutical industry needs to increase throughput in clinical development substantially. And this must be done much faster than it has in the past—time to market is often the most important factor driving pharmaceutical profitability.
A. Clinical Trials: the Now and Future Bottleneck
In U.S. pharmaceutical companies alone, a huge percentage of total annual pharmaceutical research and development funds is spent on human clinical trials. Spending on clinical trials is growing at approximately 15% per year, almost 50% above the industry's sales growth rate. Trials are growing both in number and complexity. For example, the average new drug submission to the U.S. Food & Drug Administration (FDA) now contains more than double the number of clinical trials, more than triple the number of patients, and a more than a 50% increase in the number of procedures per trial, since the early 1980s.
An analysis of the new drug development process shows a major change in the drivers of time and cost. The discovery process, which formerly dominated time to market, has undergone a revolution due to techniques such as combinatorial chemistry and high-throughput screening. The regulatory phase has been reduced due to FDA reforms and European Union harmonization. In their place, human clinical trials have become the main bottleneck. The time required for clinical trials now approaches 50% of the 15 years or so required for the average new drug to come to market.
B. The Trial Process Today
The conduct of clinical trials has changed remarkably little since trials were first performed in the 1940's. Clinical research remains largely a manual, labor-intensive, paper based process reliant on a cottage industry of physicians in office practices and academic medical centers.
1. Initiation
A typical clinical trial begins with the construction of a clinical protocol, a document which describes how a trial is to be performed, what data elements are to be collected, and what medical conditions need to be reported immediately to the pharmaceutical sponsor and the FDA. The clinical protocol and its author are the ultimate authority on every aspect of the conduct of the clinical trial. This document is the basis for every action performed by multiple players in diverse locations during the entire conduct of the trial. Any deviations from the protocol specifications, no matter how well intentioned, threaten the viability of the data and its usefulness for an FDA submission.
The clinical protocol generally starts with a cut-and-paste word-processor approach by a medical director who rarely has developed more than 1-2 drugs from first clinical trial to final regulatory approval and who cannot reference any historical trials database from within his or her own company—let alone across companies. In addition, this physician typically does not have reliable data about how the inclusion or exclusion criteria, the clinical parameters that determine whether a given individual may participate in a clinical trial, will affect the number of patients eligible for the study.
A pharmaceutical research staff member typically translates portions of the trial protocol into a Case Report Form (CRF) manually using word-processor technology and personal experience with a limited number of previous trials. The combined cutting and pasting in both protocol and CRF development often results in redundant items or even irrelevant items being carried over from trial to trial. Data managers typically design and build database structures manually to capture the expected results. When the protocol is amended due to changes in FDA regulations, low accrual rates, or changing practices, as often occurs several times over the multiple years of a big trial, all of these steps are typically repeated manually.
At the trial site, which is often a physician's office, each step of the process from screening patients to matching the protocol criteria, through administering the required diagnostics and therapeutics, to collecting the data both internally and from outside labs, is usually done manually by individuals with another primary job (doctors and nurses seeing ‘routine patients’) and using paper based systems. The result is that patients who are eligible for a trial often are not recruited or enrolled, errors in following the trial protocol occur, and patient data are often either not captured at all, or are incorrectly transcribed to the CRF from hand written medical records, and are illegible. An extremely large percentage of the cost of a trial is consumed with data audit tasks such as resolving missing data, reconciling inconsistent data, data entry and validation. All of these tasks must be completed before the database can be “locked,” statistical analysis can be performed and submission reports can be created.
2. Implementation
Once the trial is underway, data begins flowing back from multiple sites typically on paper forms. These forms routinely contain errors in copying data from source documents to CRFs.
Even without transcription errors, the current model of retrospective data collection is severely flawed. It requires busy investigators conducting multiple trials to correctly remember and apply the detailed rules of every protocol. By the time a clinical coordinator fills out the case report form the patient is usually gone, meaning that any data that was not collected or treatment protocol complexities that were not followed are generally unrecoverable. This occurs whether the case report form is paper-based or electronic. The only solution to this problem is point-of-care data capture, which historically has been impractical due to technology limitations.
Once the protocol is in place it often has to be amended. Reasons for changing the protocol include new FDA guidelines, amended dosing rules, and eligibility criteria that are found to be so restrictive that it is not possible to enroll enough patients in the trial. These “accrual delays” are among the most costly and time-consuming problems in clinical trials.
The protocol amendment process is extremely labor intensive. Further, since protocol amendments are implemented at different sites at different times, sponsors often do not know which protocol is running where. This leads to additional ‘noise’ in the resulting data and downstream audit problems. In the worst case, patients responding to an experimental drug may not be counted as responders due to protocol violations, but even count against the response rate under an intent-to-treat analysis. It is even conceivable that this purely statistical requirement could cause an otherwise useful drug to fail its trials.
Sponsors, or Contract Research Organizations (CROs) working on behalf of sponsors, send out armies of auditors to check the paper CRFs against the paper source documents. Many of the errors they find are simple transcription errors in manually copying data from one paper to the other. Other errors, such as missing data or protocol violations, are more serious and often unrecoverable.
3. Monitoring
The monitoring and audit functions are one of the most dysfunctional parts of the trial process. They consume huge amounts of labor costs, disrupt operations at trial sites, contribute to high turnover, and often involve locking the door after the horse has bolted.
4. Reporting
As information flows back from sites, the mountain of paper grows. The typical New Drug Application (NDA) literally fills a semi-truck with paper. The major advance in the past few years has the addition of electronic filing, but this is basically a series of electronic page copies of the same paper documents—it does not necessarily provide quantitative data tables or other tools to automate analysis.
C. The Costs of Inefficiency
It can be seen that this complex manual process is highly inefficient and slow. And since each trial is largely a custom enterprise, the same thing happens all over again with the next trial. Turnover in the trials industry is also high, so valuable experience from trial to trial and drug to drug is often lost.
The net result of this complex, manual process is that despite accumulated experience, it is costing more to conduct each successive trial.
In addition to being slow and expensive, the current clinical trial process often hurts the market value of the resulting drug in two important ways. First, the FDA reviews drugs on an “intent to treat” basis. That means that every patient enrolled in a trial is included in the denominator (positive responders/total treated) when calculating a drug's efficacy. However, only patients who respond to treatment and comply with the protocol are included in the numerator as positive responders. Not infrequently, a patient responds to a drug favorably, but is actually counted as a failure due to significant protocol non-compliance. In rare cases, an entire trial site is disqualified due to non-compliance. Non-compliance is often a result of preventable errors in patient management.
The second major way that the current clinical trial process hurts drug market value is that much of the fine grain detail about the drug and how it is used is not captured and passed from clinical development to marketing within a pharmaceutical company. As a result, virtually every pharmaceutical company has a second medical department that is a part of the marketing group. This group often repeats studies similar to those used for regulatory approval in order to capture the information necessary to market the drug effectively.
D. The Situation at Trial Sites
Despite the existence of a large number of clinical trials that are actively recruiting patients, only a tiny percentage of eligible patients are enrolled in any clinical trial. Physicians, too, seem reluctant to engage in clinical trials. One study by the American Society of Clinical Oncology found that barriers to increased enrollment included restrictive eligibility criteria, large amount of required paperwork, insufficient support staff, and lack of sufficient time for clinical research.
Clinical trials consist of a complex sequence of steps. On average, a clinical trial requires more than 10 sites, enrolls more than 10 patients per site and contains more than 50 pages for each patient's case report form (data entry sheet). Given this complexity, delays are a frequent occurrence. A delay in any one step, especially in early steps such as patient accrual, propagates and magnifies that delay downstream in the sequence.
A significant barrier to accurate accrual planning is the difficulty trial site investigators have in predicting their rate of enrollment until after a trial as begun. Even experienced investigators tend to overestimate the total number of enrolled patients they could obtain by the end of the study. Novice investigators tend to overestimate recruitment potential by a larger margin than do experienced investigators, and with the rapid increase in the number of investigators participating in clinical trials, the vast majority of current investigators have not had significant experience in clinical trials.
E. Absence of Information Infrastructure
Given the above state of affairs, one might expect that the clinical trials industry would be ripe for automation. But despite the desperate need for automation, remarkably little has been done.
While the pharmaceutical industry spends hundreds of millions of dollars annually on clinical information systems, most of this investment is in internal custom databases and systems within the pharmaceutical company; very little of this technology investment is at the physician office level. Each trial, even when conducted by the same company or when testing the same drug, is usually a custom collection of sites, procedures and protocols. More than half of trials are conducted for the pharmaceutical industry by Contract Research Organizations (CROs) using the same manual systems and custom physician networks.
The clinical trials information technology environment contributes to this situation. Clinical trials are information-intensive processes—in fact, information is their only product. Despite this, there is no comprehensive information management solution available. Instead there are many vendors, each providing tools that address different pieces of the problem. Many of these are good products that have a role to play, but they do not provide a way of integrating or managing information across the trial process.
The presently available automation tools include those that fall into the following major categories:                Clinical data capture (CDC)        Site-oriented trial management        Electronic Medical Records (EMRs) with Trial-Support Features        Trial Protocol design tools        Site-sponsor matching services        Clinical data management.        
Clinical Research Organizations (CROs) and Site Management Organizations (SMOs) also provide some information services to trial sites and sponsors.
1. Clinical Data Capture (CDC) Products
These products are targeted at trial sites, aiming to improve speed and accuracy of data entry. Most are rapidly moving to Web-based architectures. Some offer off-line data entry, meaning that data can be captured while the computer is disconnected from the Internet. Most companies can point to half a dozen pilot sites and almost no paying customers.
These products do not create an overall, start-to-finish, clinical trials management framework. These products also see “trial design” merely as “CRF design,” ignoring a host of services and value that can be provided by a comprehensive clinical trials system. They also fail to make any significant advance over conventional methods of treating each trial as a “one-off” activity. For example, the companies offering CDC products continue to custom-design each CRF for each trial, doing not much more than substituting HTML code for printed or word-processor forms.
2. Site-Oriented Trial Management
These products are targeted at trial sites and trial sponsors, aiming to improve trial execution through scheduling, financial management, accrual, visit tracking. These products do not provide electronic clinical data entry, nor do they assist in protocol design, trial planning for sponsors, patient accrual or task management.
3. Electronic Medical Records (EMR) with Trial-Support Features
These products aim to support patient management of all patients, not just study patients, replacing most or all of a paper charting system. Some EMR vendors are focusing on particular disease areas, with KnowMed being a notable example in oncology.
These products for the most part do not focus specifically on the features needed to support clinical trials. They also require major behavior changes affecting every provider in a clinical setting, as well as requiring substantial capital investments in hardware and software. Perhaps because of these large hurdles, EMR adoption has been very slow.
4. Trial Protocol Design Tools
These products are targeted at trial sponsors, aiming to improve the protocol design and program design processes using modeling and simulation technologies. One vendor in this segment, PharSight, is known for its use of PK/PD (pharmacokinetic/pharacadynamic) modeling tools and is extending its products and services to support trial protocol design more broadly.
None of the companies offering trial protocol design tools provide the host of services and value that can be provided by a comprehensive clinical trials system.
5. Trial Matching Services
Some recent Web-based services aim to match sponsors and sites, based on a database of trials by sponsor and of sites' patient demographics. A related approach is to identify trials that a specific patient may be eligible for, based on matching patient characteristics against a database of eligibility criteria for active trials. This latter functionality is often embedded in a disease-specific healthcare portal such as cancerfacts.com.
6. Clinical Data Management
Two well-established products, Domain ClinTrial and Oracle Clinical, support the back-end database functionality needed by sponsors to store the trial data coming in from CRFs. These products provide a visit-specific way of storing and querying study data. The protocol sponsor can design a template for the storage of such data in accordance with the protocol's visit schema, but these templates are custom-designed for each protocol. These products do not provide protocol authoring or patient management assistance.
7. Statistical Analysis
The SAS Institute (SAS) has defined the standard format for statistical analysis and FDA reporting. This is merely a data format, and does not otherwise assist in the design or execution of clinical trial protocols.
8. Site Management Organizations (SMO)
SMOs maintain a network of clinical trial sites and provide a common Institutional Review Board (IRB) and centralized contracting/invoicing. SMOs have not been making significant technology investments, and in any event, do not offer trial design services to sponsors.
9. Clinical Research Organizations (CROs)
CROs provide, among other services, trial protocol design and execution services. But they do so on substantially the same model as do sponsors: labor-intensive, paper-based, slow, and expensive. CROs have made only limited investments in information technology.
F. The Need for a Comprehensive Clinical Trials System
It can be seen that the current information model for clinical trials is highly fragmented. This has led to high costs, “noisy” data, and long trial times. Without a comprehensive, service-oriented information solution it is very hard to get away from the current paradigm of paper, faxes and labor-intensive processes. And it has become clear that simply “throwing more bodies” at trials will not produce the required results, particularly as trial throughput demands increase. A new, comprehensive model is required.